EP0026813A2 - (N-phosphonoacétyl-L-aspartato) (1,2 diaminocyclohexane) platine (II),et sels de sodium, potassium ou lithium, leur préparation et compositions pharmaceutiques les contenant - Google Patents

(N-phosphonoacétyl-L-aspartato) (1,2 diaminocyclohexane) platine (II),et sels de sodium, potassium ou lithium, leur préparation et compositions pharmaceutiques les contenant Download PDF

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Publication number
EP0026813A2
EP0026813A2 EP80104102A EP80104102A EP0026813A2 EP 0026813 A2 EP0026813 A2 EP 0026813A2 EP 80104102 A EP80104102 A EP 80104102A EP 80104102 A EP80104102 A EP 80104102A EP 0026813 A2 EP0026813 A2 EP 0026813A2
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EP
European Patent Office
Prior art keywords
platinum
diaminocyclohexane
phosphonacetyl
aspartato
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP80104102A
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German (de)
English (en)
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EP0026813A3 (en
EP0026813B1 (fr
Inventor
Sandra Jan Meischen
Glen Roy Gale
Marion Benton Naff
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United States Department of Commerce
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United States Department of Commerce
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Priority to AT80104102T priority Critical patent/ATE9700T1/de
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Publication of EP0026813A3 publication Critical patent/EP0026813A3/en
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Publication of EP0026813B1 publication Critical patent/EP0026813B1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl

Definitions

  • N-phosphonacetyl-L-aspartato (1,2-diaminocyclohexane)-platinum(II) or Alkali Metal Salt
  • X is Na + , K + , Li + , or H
  • N-phosphonacetyl-L-aspartato (1,2-diaminocyclohexane)platinum(II) or alkali metal salt thereof has shown antitumor activity in animals such as activity against murine leukemia L1210. Additionally, this agent is used against B-16 and Colon 38 tumors and also Ehrlich ascites tumor.
  • CY cyclophosphamide
  • HU hydroxyurea
  • the preferred ratio of the present compound to cisplatin is about 10:1 with a range of about 10:1 to 1:10 in mg/kg of body weight.
  • the formula on the left hand side it may be varied as monodentate, such as cisplatin containing a single amine group proceeding from the ring, or bidentate, such as the present compound.
  • the saturated cyclo ring may be C 4 or C 5 -C 7 in addition to the present cyclohexane.
  • aromatic where the aromatic may be substituted or unsubstituted.
  • Monodentate aromatic where the aromatic may be substituted or unsubstituted.
  • the present platinum compound may be prepared by reacting the known L-aspartic acid, N-(phosphonacetyl-) disodium salt (PALA; NSC-224131), with dinitrato (1,2-diaminocyclohexane)platinum(II) (NSC-239851).
  • PAA N-(phosphonacetyl-) disodium salt
  • NSC-239851 dinitrato (1,2-diaminocyclohexane)platinum(II)
  • N-phosphonacetyl-L-aspartato (1,2-diaminocyclohexane)platinum(II) may be combined in multiple drug regimen with substantially improved yield cures over the parent compounds.
  • the compound denoted Pt-268 may be combined in a dual regimen with cyclophosphamide (CY), hydroxyurea (HU), and cisplatin.
  • the compounds according to the invention are effective in multiple drugs when combined with cis-dichlorodiamine platinum-(II) in a ratio of about 10:1 1 by weight percent, or with cyclophosphamide where the ratio of platinum (II) /cyclophosphamide is about 10:1 by weight percent, or with hydroxyurea where the ratio of platinum(II)/hydroxyurea is about 1:6 by weight percent.
  • NSC numbers in this application are the official numbers made public by the National Cancer Institute and the following numbers are particularly utilized.
  • Fig. 1 shows the effect of N-phosphonacetyl-L-aspartato (l,2-diaminocyclohexane)platinum(II) [Pt-268] on life spans of mice bearing L1210 leukemia.
  • Mice received 10 6 L1210 cells on Day 0 via intraperitoneal route.
  • Pt-268 was given intraperitoneally on Day 1 only in 5% glucose solution.
  • Fig. 2 shows the effect of Pt-268 on life spans of mice bearing L1210 leukemia.
  • Mice received 10 6 L1210 cells on Day 0 via intraperitoneal route.
  • Pt-268 was given intraperitoneally on Days 1, 5, and 9 in 5% glucose solution.
  • Numbers adjacent to symbols number of >60- day survivors in each group of 10 animals.
  • Control survival time 203 hours.
  • Fig. 4 shows the effect of Pt-268 when used in combination with cisplatin (NSC-119875). Mice were given an inoculum of 10 6 L1210 cells, One group received Pt-268 on Day 3; another group received cisplatin on Days 3, 4, 5, and 6; and a third group received the two drugs in combination on the same schedule. This third group of animals showed an increased median life span of 25 days over the control group with a cure rate ( >50-day survivors) of 50%.
  • step (a) recites the conventional preparation of cisplatin (NSC-194814) and in steps (b) and (c) 1.38 grams (4.6 mmoles) of PALA [N-(phosphonacetyl-)disodium salt] was added to 1.6 grams (3.7 mmoles) of dinitrato(1,2-diami.nooyclohexane)-platinum(II) (NS C -239851). These reactants were initially dissolved in a minimum of distilled water prior to mixing. The reaction mixture was stirred overnight at room temperature with a flow of filtered air to facilitate evaporation. The solid material was collected and dissolved in 20 ml of distilled water.
  • the present compound has been tested alone and in combination with cyclophosphamide and hydroxyurea. It is believed that there is a substantial advantage synergistically in the combination of Pt-268 and cyclophosphamide although the advantage as with hydroxyurea was minimal. In the ternary system with Pt-268 plus cyclophosphamide plus hydroxyurea, there is a substantial synergistic advantage over the binary system with cyclophosphamide and the results of this multiple therapy are set out in Fig. 3.
  • the PALA group apparently dissociates or leaves from the Pt-268 complex rather slowly.
  • Pt-268 is dissolved in 0.9% NaCl solution
  • displacement of the PALA with chlorides as evidenced by the appearance of an insoluble precipitate of dichloro(1,2-diaminocyclohexane)platinum(II) (NSC-194814)
  • NSC-194814 an insoluble precipitate of dichloro(1,2-diaminocyclohexane)platinum(II)
  • a minor platinum-PALA component was faintly observed at R f ⁇ 0.54.
  • the N-phosphonacetyl-L-aspartato(1,2-diamino- chclohexane)platinum(II) complex (Pt-268; NSC-314926) was dissolved in 5% glucose and tested for its activity in the L1210 leukemia in mice.
  • LD 50 was determined in tumored BDF 1 mice and was found to be 180 mg/kg.
  • the BDF 1 mice received 10 6 L1210 leukemia cells by I.P. injection on Day 0 and were divided into groups of 10, including a control group of 40 mice. The treated groups were treated on Day 1 only at different dose levels from 10 mg/kg to 200 mg/kg or treated on Days 1, 5, and 9 at dose levels from 2.5 mg/kg to 50 mg/kg.
  • Fig. 1 shows the dose-response curve for Day 1 only treatment.
  • Fig. 2 summarizes the results obtained from a dose schedule in which Pt-268 was administered on Days 1, 5, and 9. The optimal dose in this study was approximately 20 mg/kg when given at this regimen.
  • N-phosphonacetyl-L-aspartate (PALA; N SC-224131) as received from the National Cancer Institute had a purity of 87 ⁇ 2% and consisted of 64% disodium salt and 26% trisodium salt, The remainder was water and ethanol. Therefore, the stoichiometry was adjusted so that 2.5 grams .(8.36 mmoles) of the PALA would be added to 3.55 grams (8.2 moles) of dinitrato(l,3-diaminocyclohexane)platinum(II) (NSC-239851).
  • NSC-268252 The synthesis of NSC-268252 is described in Schwartz et al., Cancer Treatment Report, 61:1519-1525, 1977.
  • the solutions were allowed to react with the resins and were then filtered from the resins, combined, and the mixture was transferred to the flask of a vacuum flash evaporator. Upon removal of all the water, the product was dissolved in,30 ml of water, filtered, and 400 ml of absolute ethanol was added to precipitate the white product. Yield of NSC-328005 was approximately 30% of the theoretical value.
  • N SC-328005 can also be used as the starting material for producing the alkali metal salt form. This is done by titrating with a known amount of alkali metal base such as sodium bicarbonate.
  • the chart below shows survival times of BDF 1 mice bearing the Ehrlich ascites carcinoma.
  • Mice received an intraperitoneal inoculation of 10 7 tumor cells on Day 0; treatment was by the intraperitoneal route on Day 1 only.
  • NSC-314926 [N-phosphonacetyl-L-aspartato(1,2-diaminocyclohexane)platinum(II)] was dissolved in 5% dextrose solution. There were 10 mice per group.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP80104102A 1979-07-17 1980-07-15 (N-phosphonoacétyl-L-aspartato) (1,2 diaminocyclohexane) platine (II),et sels de sodium, potassium ou lithium, leur préparation et compositions pharmaceutiques les contenant Expired EP0026813B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT80104102T ATE9700T1 (de) 1979-07-17 1980-07-15 (n-phosphonoacetyl-l-aspartato) (1,2diaminocyclohexan)-platin (ii) und natrium-, kalium- oder lithiumsalze, ihre herstellung und pharmazeutische zusammensetzungen, die sie enthalten.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US5828779A 1979-07-17 1979-07-17
US58287 1979-07-17
US155531 1980-06-09
US06/155,531 US4284579A (en) 1979-07-17 1980-06-09 (N-Phosphonacetyl-L-aspartato)(1,2-diaminocyclchexane)platinum(II) or alkali metal salt

Publications (3)

Publication Number Publication Date
EP0026813A2 true EP0026813A2 (fr) 1981-04-15
EP0026813A3 EP0026813A3 (en) 1982-02-03
EP0026813B1 EP0026813B1 (fr) 1984-10-03

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EP80104102A Expired EP0026813B1 (fr) 1979-07-17 1980-07-15 (N-phosphonoacétyl-L-aspartato) (1,2 diaminocyclohexane) platine (II),et sels de sodium, potassium ou lithium, leur préparation et compositions pharmaceutiques les contenant

Country Status (8)

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US (1) US4284579A (fr)
EP (1) EP0026813B1 (fr)
JP (1) JPS56500849A (fr)
CA (1) CA1151663A (fr)
DE (1) DE3069356D1 (fr)
ES (1) ES8105746A1 (fr)
IL (1) IL60575A (fr)
WO (1) WO1981000256A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0130482A1 (fr) * 1983-06-20 1985-01-09 Research Corporation Complexes de platine de diaminocyclohexane, leur procédé de préparation et compositions pharmaceutiques les contenant
EP0284197A1 (fr) * 1987-02-20 1988-09-28 Tanabe Seiyaku Co., Ltd. Complexes organiques de platine et leur procédé de préparation
EP0281412A3 (fr) * 1987-03-06 1988-12-21 Tanabe Seiyaku Co., Ltd. Complexes organiques de platine, compositions pharmaceutiques les contenant et leur procédé de préparation
US5657470A (en) * 1994-11-09 1997-08-12 Ybm Technologies, Inc. Personal computer hard disk protection system

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR75598B (fr) * 1980-04-29 1984-08-01 Sanofi Sa
US4562275A (en) * 1984-03-23 1985-12-31 Bristol-Myers Co. Antitumor platinum complexes
US4665210A (en) * 1984-12-17 1987-05-12 American Cyanamid Company Platinum complexes of aliphatic tricarboxylic acids
US4739087A (en) * 1985-01-10 1988-04-19 Bristol-Myers Company Antineoplastic platinum complexes
JPS6296A (ja) * 1985-03-06 1987-01-06 Sumitomo Pharmaceut Co Ltd 脂溶性白金（２）錯体
US4658047A (en) * 1985-09-27 1987-04-14 The United States Of America As Represented By The Department Of Health And Human Services Method of preparing 1,2-diaminocyclohexane tetrachloro platinum (IV) isomers
US5384127A (en) * 1985-10-18 1995-01-24 Board Of Regents, The University Of Texas System Stable liposomal formulations of lipophilic platinum compounds
US5041581A (en) * 1985-10-18 1991-08-20 The University Of Texas System Board Of Regents Hydrophobic cis-platinum complexes efficiently incorporated into liposomes
US4670458A (en) * 1986-01-31 1987-06-02 American Cyanamid Company Hydroxylated 1,2-diaminocyclohexane platinum complexes
EP0376959B1 (fr) * 1987-07-17 1993-03-24 Georgetown University Produits pharmaceutiques a base de platine
US4895935A (en) * 1987-07-17 1990-01-23 Georgetown University Platinum pharmaceuticals
US4895936A (en) * 1987-07-17 1990-01-23 Georgetown University Platinum pharmaceuticals
US4956459A (en) * 1987-07-17 1990-09-11 Georgetown University Platinum compounds suitable for use as pharmaceuticals
US4946954A (en) * 1989-01-17 1990-08-07 Georgetown University Platinum pharmaceutical agents
KR0164460B1 (ko) * 1995-10-02 1999-03-20 김은영 고분자 백금 착화합물, 그의 제조방법 및 그를 유효성분으로 하는 항암제
HUP0103314A3 (en) * 1998-08-05 2002-07-29 Aventis Pharma Sa Use of camptothecin derivatives, with reduced gastrointestinal toxicity
AU775373B2 (en) 1999-10-01 2004-07-29 Immunogen, Inc. Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents
KR100363394B1 (ko) * 2000-08-21 2002-12-05 한국과학기술연구원 온도감응성을 갖는 포스파젠삼량체-백금착물 복합체, 그의제조방법 및 그를 함유하는 항암제 조성물
US7138520B2 (en) * 2003-01-13 2006-11-21 Massachusetts Institute Of Technology Coordination complexes having tethered therapeutic agents and/or targeting moieties, and methods of making and using the same
KR20040074857A (ko) * 2003-02-19 2004-08-26 학교법인 이화학당 Ｎ-치환 아미노디카복실산의 백금(ⅱ) 착물 및 그 제조방법
WO2006091790A1 (fr) * 2005-02-23 2006-08-31 Xenoport, Inc. Composes contenant du platine presentant une activite cytostatique, synthese et procedes d'utilisation correspondants

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH605550A5 (fr) * 1972-06-08 1978-09-29 Research Corp
US4115418A (en) * 1976-09-02 1978-09-19 Government Of The United States Of America 1,2-diaminocyclohexane platinum (ii) complexes having antineoplastic activity
JPS6041077B2 (ja) * 1976-09-06 1985-09-13 喜徳 喜谷 １，２‐ジアミノシクロヘキサン異性体のシス白金（２）錯体
US4137248A (en) * 1977-08-29 1979-01-30 The United States Of America As Represented By The Department Of Health, Education And Welfare Compound, 4-carboxyphthalato(1,2-diaminocyclohexane)-platinum(II) and alkali metal salts thereof
AU520966B2 (en) * 1977-11-14 1982-03-11 Starks Associates, Inc. N-phosphonoacetyl-l-aspartic and derivatives
GB2019397B (en) * 1978-04-20 1982-10-27 Johnson Matthey Co Ltd Pt 2 and 4 complexes with amino-acids

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0130482A1 (fr) * 1983-06-20 1985-01-09 Research Corporation Complexes de platine de diaminocyclohexane, leur procédé de préparation et compositions pharmaceutiques les contenant
EP0284197A1 (fr) * 1987-02-20 1988-09-28 Tanabe Seiyaku Co., Ltd. Complexes organiques de platine et leur procédé de préparation
US4882447A (en) * 1987-02-20 1989-11-21 Tanabe Seiyaku Co., Ltd. Novel organic platinum complex and process for the preparation thereof
EP0281412A3 (fr) * 1987-03-06 1988-12-21 Tanabe Seiyaku Co., Ltd. Complexes organiques de platine, compositions pharmaceutiques les contenant et leur procédé de préparation
US4886894A (en) * 1987-03-06 1989-12-12 Tanabe Seivaku Co., Ltd. Novel Organic platinum complex and process for the preparation thereof
AU604299B2 (en) * 1987-03-06 1990-12-13 Tanabe Seiyaku Co., Ltd. Novel organic platinum complex and process for the preparation thereof
US5657470A (en) * 1994-11-09 1997-08-12 Ybm Technologies, Inc. Personal computer hard disk protection system

Also Published As

Publication number Publication date
CA1151663A (fr) 1983-08-09
IL60575A (en) 1983-10-31
EP0026813A3 (en) 1982-02-03
ES493474A0 (es) 1981-06-16
EP0026813B1 (fr) 1984-10-03
ES8105746A1 (es) 1981-06-16
DE3069356D1 (en) 1984-11-08
US4284579A (en) 1981-08-18
WO1981000256A1 (fr) 1981-02-05
JPS56500849A (fr) 1981-06-25

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